Peptidyl alpha-keto esters and alpha-keto amides are broadly useful in medicinal chemistry as potent inhibitors of proteolytic enzymes such as serine and cysteine proteases. Their cellular targets include calpain (a calcium-activated cysteine protease that has been implicated in stroke, Alzheimer's disease and muscular dystrophy), caspase (a cysteine protease that plays a role in apoptosis), and thrombin (a serine protease that converts fibrinogen to fibrin). In particular, beta-amino alpha-keto amide isosteres are of interest as viral protease inhibitors for the treatment of HIV and hepatitis C.
Conventional routes to beta-amino alpha-keto amides invariably rely on the one-carbon homologation of an N-protected alpha-amino acid derivative. A process using cyanide as the one-carbon addend has been described by Manoz et al. in Bioorg. Med. Chem., 2, 1085-1090 (1994). In this example, epimerization occurs at the nitrogen-bearing carbon during the subsequent oxidation step, affording the alpha-keto amide as a 1:1 mixture of diastereomers. In contrast, a stereospecific process involving the addition of an isonitrile to an N-protected alpha-amino aldehyde has been described by Banfi et al. in Tetrahedron Lett., 43, 4067-4069 (2002). A second stereospecific process involves the addition of (cyanomethylene)phosphorane to an amino acid derivative, as described by Wasserman et al. in J. Org. Chem., 62, 8972-8973 (1997). This route initially provides an acyl cyanophosphorane intermediate A which is converted to the beta-keto amide product B upon ozonolysis and treatment with a primary amine.
These one-carbon homologation routes are most useful when the required alpha-amino acid is a readily available “natural” amino acid. However, a general limitation occurs when the requisite starting material is an “unnatural” (non-proteinaceous) amino acid. Such amino acids are themselves prepared by expensive multi-step synthetic sequences and in some case are not available in sufficient quantities to support commercial drug manufacture.
An additional problem is the sensitivity of the beta-amino alpha-keto amide functionality toward both acidic and basic reagents. This can interfere with incorporation of the molecule into a peptide. A solution to this problem is described by Papanikos et al. in J. Combin. Chem., 6, 181-195 (2004). In this process, a beta-amino alpha-keto amide is first synthesized in enantiomerically pure form and is then protected as a 1,3-dithiolane derivative in a separate step. After incorporation into a peptide, the dithiolane functional group is removed, unmasking the alpha-keto amide functionality.
A related approach is described by Powers et al. in J. Med. Chem., 36, 3472-3480 (1993). In Powers' approach, an alpha-keto ester is first protected as a dithiolane derivative and is then converted to an alpha-keto amide in subsequent transformations. However, this process is not stereospecific.
As is clear from the above discussion, it would be advantageous to access enantiomerically pure dithiolane-protected alpha-keto amides via a route that does not require the availability of the corresponding alpha-amino acid.
A process for enantioselective addition of a 6-membered ring dithiane derivative to an enantiomerically pure sulfinimine has been described by Davis et al. in Tetrahedron Lett., 49, 870-872 (2008). However, this reaction fails when the substituent on the carbon atom between the two sulfur atoms in the dithiane derivative is an electron-withdrawing functional group, e.g., an ester or amide group.